DR. SIMPSON is Executive Associate Dean for Academic Affairs, and Professor of Obstetrics and Gynecology and Human and Molecular Genetics, Florida International University College of Medicine, Miami, FL. He is Past President of the Society for Gynecologic

Joe Leigh Simpson, MD

Incorporating genetics into practice was once straightforward for our specialty. Prenatal genetic diagnosis was mostly relevant to women over age 35 at delivery, plus those in a particular ethnic group. Single genes seemed unlikely to be causative for more than exceptional cases. For example, searches for individual genes causing polycystic ovary syndrome (PCOS) and endometriosis floundered and proved hard to find for common cancers. We knew increased risks existed in first-degree relatives for some women with these conditions, but the etiologies were unclear and risks in these relatives were generally less than 5%. We invoked polygenic inheritance: many genes of small affect when present individually could cumulatively influence the presence or absence of the condition. In gynecological cancers, the applicable conditions involved breast, ovary and endometrium. However, management was, after all, the same whether the cause was familial or not. So, why bother delving into the arcane science of genetics?

Well, the genomic era and facile ability to sequence an individual’s cell- or tissue-derived DNA has upended our comfort zone. No longer can we remain aloof.

 in this issue by Leslie M. Randall MD, MAS, and Katherine Coakley, MD,  illustrates well the new reality. New conceptual approaches are here today for gynecological cancer and soon will be applicable for other conditions. With the cost of gene sequencing decreasing (perhaps one-third or less than an in vitro fertilization cycle) and the ease of bioinformatic interpretation increasing correspondingly, we can expect precision medicine to be inculcated in practices. We cannot hide any longer.

To appreciate our new responsibility, let’s take a step back and consider gynecological cancer and its heritability. We have long known that familial cases existed, but classic autosomal-dominant pedigrees were rare and the genetic mechanism was unknown. The relatively low recurrence risk in first-degree relatives dissuaded some of a single-gene etiology, consistent with reasoning that individuals with the same histology must have the same condition. Of course, we now know that all common, adult-onset disorders are heterogenous in their genetic etiology. Different genes and non-genetic etiologies contribute to the aggregate sum of cases. In gynecological cancer, the role of single mutant genes is now well-illustrated by hereditary breast and ovarian cancer (HBOC) and Lynch syndrome, an important cause of endometrial and colon cancer.

Clinically, some cases of gynecological cancer appear to be inherited, whereas others are sporadic. This was traditionally explained based on the assumption that cancer arises-whether inherited or not-by sequential mutations. The once touted “two-hit” hypothesis is less sacrosanct than before, but multiple hits are unequivocally involved. All this differs from genetic disorders like sickle cell anemia or cystic fibrosis, which require only a single “hit” in the requisite gene.

In heritable cancers in any organ, it is assumed that a parent has transmitted a mutant gene to offspring, even if he/she is asymptomatic. But there still must occur a second (or more) mutagenic “hit” for cancer to originate. One does not have to have a transmissible mutation to develop cancer, but if a person has one of the two or more required mutations, she has an unfortunate head start. In such cases, age at cancer onset is earlier than if two somatic mutations are required. Given that the transmitted mutation would have been in the embryo, the mutant gene would be present throughout the body (germline). Thus, it can be conveniently detected in the patient’s blood.

In contrast, the second hit must be specific to the organ (breast, ovary, endometrium) that will manifest cancer. Thus, one can detect this somatic mutation (not transmitted) only in the organ affected. This type of testing becomes applicable if genetic characteristics of the tumor dictate specific therapy.

In the genomic era, it became possible to sequence individuals and tissues, providing novel information concerning genes altered in a specific condition. Among the cohort of women with HBOC and Lynch syndrome it was possible to identify causative genes and determine the number of individuals having those genes. For example, 70% of patients with HBOC have 

 mutations. Faulty DNA repair genes-mismatch repair (MMR) genes 

-are causative in Lynch syndrome. Other mutations play roles, but less frequently.

Where do we stand now and what is different?

Simply put, the pedigree is now relevant. If a patient has a known transmissible mutation, her family members need to be tested. Family members, distant or close, qualify. If a clinically normal family member proves to have the (germline) mutation, a surveillance program should be initiated on the assumption that a subsequent “hit” will result in cancer. We have multiple laboratory options for testing for gynecological cancers. Should testing stop with common markers for the causative germline mutations (

; MMR)? Should multigene panels including less common mutations be ordered? Should we jump to whole-exome sequencing (all protein coding genes), which is actually less daunting and less expensive than one might imagine? I predict that whole-exome or genome sequencing will soon be preferable, not just for cancer testing but probably for all of us. Imagine the advantages of recognizing pharmacogenetic susceptibilities to avoid idiosyncratic drug reactions!

 In the 1990s, for good strategic reasons, the American College of Obstetricians and Gynecologists
established the goal of adding generalist medicine to our surgical background. Although a laudable goal, in my opinion, only a partial success. I suspect that our hearts were not in it. (After all, we went into ob/gyn to avoid having to deal ubiquitously with these conditions!) We have returned to this question in 2018, but now we really do bear the responsibilities.

Extending cancer testing to asymptomatic family members and following with surveillance truly is our domain. Actually, cancer testing is a good place to get into a comfort zone. We can predict that genetic differences will be correlated with different treatment protocols and different outcomes. We can anticipate that other gynecological conditions, such ovarian stimulation, endometriosis, and PCOS, will need to be approached in similar fashion.

For now, you should consider gynecologic cancer testing for HBOC and Lynch syndrome part of your day’s work.

Articles

Ob/gyns have a responsibility and can no longer be passive in this genomic era.

HBOC and Lynch syndrome testing: All in a day’s work

Once upon a time, medical advertising was considered quite inappropriate. In fact, physicians over a certain age may recall when directly communicating with the general public was limited to the Yellow Pages or perhaps understated announcements concerning retirements or new partners. This thinking now seems terribly antiquated, so last century. One is almost expected to advertise, and with great elan. Some may wistfully recall simpler times, but that was before we had the internet. 

And it's not just physicians who are advertising. Hospitals and pharmaceutical companies likewise peddle their wares to the public with great flare. Advertisements behind home plate remind us where sports injuries can be treated; time outs and injury updates during football games are sponsored by health systems. Clever television ads encourage backyard quarterbacks to benefit from sildenafil. It would be quixotic for us to resist this trend. The train has long since left the station. 

The latest direct-to-consumer (DTC) barrage, however, seems a bit more pernicious. The situation started with burgeoning genetic discoveries which, coupled with meteoric increases in technology, have permitted us to determine the risk of developing many disorders or suffering drug reactions. Testing for two variants in the cytochrome P-450 2C9 gene (CYP2C9) and one in the vitamin K epoxide complex 1 gene (VKORC1), for instance, can identify 50% of individuals who will experience hypersensitivity or resistance to warfarin.

 Similarly abacavir is a highly effective drug for managing human immunodeficiency virus (HIV) – infected patients, but 5% to 8% experience potentially fatal hypersensitivity. This can be accurately predicted on the basis of allele HLA-B*5701, the presence of which contraindicates abacavir therapy.

There seems to be a market for these DTC kits. One company offers a profile for prostate cancer, touting its ability to predict up to a 5-fold increased risk, or 9-fold if family history is taken into account. Another kit offers to assess one's nutritional needs. Even the sequence of the entire genome, or selected genes, can be ordered, a process approved by regulatory authorities in California.  

Given this onslaught of information, it is inevitable that at least some of our patients will be interested. Yet, they may not appreciate certain unintended consequences. An "adverse" genetic profile does not confer certainty of disease, nor the converse. What role then, should we obstetrician-gynecologists play in DTC testing?  

First, accept that patients will have DTC performed with or without our approval, and often inappropriately. Low risk patients are indeed influenced by media ads.

  Thus, we will be presented with test results post hoc, asked to explain their meaning, and recommend often unavailable preventative measures. 

Second, encourage patients to tell us of their interest in a given DTC test in advance, rather than merely waiting to present us with results. Does the patient truly understand that a DTC test may not provide a definitive answer, but only a relative risk? Or, that even a 20-fold increase in relative risk may confer a very low absolute risk? Or, that there are no treatment options at this time? Such discussion may result in ardor for a given test diminishing. Young women often ask for amniocentesis in order to have a "genetically perfect child". When they learn such a request is unrealistic, interest wanes.  

Third, the obstetrician-gynecologist needs to determine the extent to which he or she is comfortable in interpreting a given DTC result. If the disorder in question is outside our discipline, we could demur. Not so for DTC results concerning conditions like ovarian cancer. The American College of Medical Genetics offers useful minimal requirements for providers assessing direct-to-consumer (DTC) tests.

Patients are going to have direct-to-consumer genetic tests done, regardless of our position on the subject. At the very least, we can offer them sound advice on the matter.

DTC genetic testing: What do you tell patients?

Preimplantation genetic diagnosis (PGD) is a major advance, one that has given us the ability to diagnose a genetic disorder before implantation at 6 days postconception. For more than a decade, it's been an important addition to prenatal genetic diagnosis.

  Assisted reproductive technology (ART) is required, most commonly in vitro fertilization (IVF), followed by removing and analyzing a single blastomere at the eight-cell stage (3 days). Embryos subsequently classified as unaffected by genetic defects are transferred, and affected embryos are not. Analysis of polar bodies can usually accomplish the same goal. Because ART is required and the process is expensive and stressful, some indications are controversial, and guidelines are not always consistent or followed.

  My goal here is to explain the current indications for PGD, addressing these controversies. 

Avoiding clinical termination of affected pregnancies   

Of all the couples in the United States undergoing traditional prenatal genetic diagnosis, only half are prepared to terminate a pregnancy if their fetus is deemed abnormal. So on the one hand, many couples wish to be reassured that their fetus is normal, but on the other, they are not prepared to terminate an affected clinical pregnancy. Only PGD allows these couples the option of avoiding an abnormal child. PGD to avoid clinical termination has been a common attraction since the procedure was introduced in the 1990s; almost half of European couples undergoing PGD cite this as a reason.

  Even couples who have no religious objections to termination find traditional prenatal diagnosis daunting when termination becomes necessary in more than one pregnancy. In couples at risk for autosomal recessive disorders (e.g., cystic fibrosis), it's not rare to have consecutive fetuses affected (1/4 × 1/4 = 1/16). 

When pregnancy involves a prospective parent at risk for an adult-onset autosomal dominant disorder, PGD is the only pragmatic approach. This at-risk parent may be clinically normal but have a mutant gene not yet clinically manifested. Typically, the parent's at-risk status came to light because one of the prospective parents has a mother or father with such a disorder. If a patient's parent has the autosomal dominant disorder Huntington disease, for example, the risk for any given fetus is 1 in 4 (1 in 2 that the prospective parent is affected times 1 in 2 that, if so affected, the mutant gene will be transmitted). 

The at-risk parent may not wish to learn of his/her genotype, but may still want to avoid transmitting the mutant gene to the couple's offspring. Through PGD, the at-risk adult can do so, remaining unaware of his or her own status. The strategy requires screening all embryos, transferring only those unaffected, and never disclosing information on any individual embryo. The scenario must be repeated in subsequent cycles, even if tests reveal the at-risk parent to be unaffected. Otherwise, at-risk patients would readily deduce their genotype. 

Another unique capability of PGD involves identifying HLA-compatible embryos for transfer. Suppose a couple desiring a pregnancy has had a child with a lethal autosomal recessive disorder characterized by bone marrow failure. If stem cell transplantation could repopulate the child's bone marrow with genetically normal precursors, the affected sibling would be able to survive. Stem cell transplantation is highly successful if HLA-compatibility exists between donor and recipient, but considerably less successful when it does not. 

A sibling is the most likely source for HLA-compatible stem cells-including cells from a newborn sibling's umbilical cord blood. Although amniocentesis or chorionic villus sampling can identify HLA- compatible fetuses, only 1 of 4 fetuses 

 HLA compatible. The prospective fetuses will usually also be at risk for the autosomal recessive disorder causing the sibling's bone marrow failure; but 3 of 4 fetuses would be normal. What's more, the overall likelihood of a genetically normal HLA-compatible fetus is only 3 in 16 (i.e., a 1 in 4 likelihood of HLA-compatibility multiplied by a 3 in 4 likelihood of being unaffected). Only PGD provides a practical method for yielding an unaffected and HLA-compatible embryo. The most common indications are  β-thalassemia, Fanconi anemia, Wiskott-Alderich syndrome, and acute leukemia.

  Aneuploidy can be determined on the same embryos.

Among the clinical issues to consider: Should PGD aneuploidy testing be offered to women of advanced maternal age?

Preimplantation genetic diagnosis: Which patients to test and other controversies

But it is possible, because prenatal screening just isn't so perfect and some genetic conditions are relatively common. One in 800 liveborns has DS, and the incidence increases with advanced maternal age. One in every 2,500 Caucasians of Northern European or Ashkenazi Jewish ancestry has CF. Even if screening produces negative results, there 

 still reason for expectant parents to worry. The risk is far lower, to be sure, but affected cases do occur. 

How, exactly, do we find ourselves in the unenviable position of bearing bad news to a couple who believed their pregnancy was normal? The problem is our failure to help patients understand the difference between screening and case detection.  

In genuine genetic screening, by contrast, we acknowledge that not all cases will be detected. We accept detection rates of only 80%-and failure rates of 20%. But there are also certain prerequisites: a reliable assay, the possibility of altering management by curing a disease (neonatal screening) or permitting reproductive options, ability to address unexpected problems, and a favorable cost:benefit ratio.  

The standard of care for DS screening is analysis of selected serum analytes and measurement of nuchal translucency. Women whose risk is above a certain threshold-usually the 1 in 270 mid-trimester risk for a 35-year-old-are also offered chorionic villus sampling (CVS) or amniocentesis. Approximately 1 in 20 to 25 such invasive procedures will detect a fetus with DS.  

If we performed first-trimester CVS on just 5% of the women who have first-trimester screening, we could detect 87% to 93% of cases of DS. In the second trimester, using a triple screen would yield a 70% detection rate, and using a quadruple screen would yield a detection rate of 80%. The rate would increase to 95% with sequential screening in the first and second trimesters, if we could achieve full patient compliance. In fact, we could detect incrementally more cases of DS if we were willing to perform amniocentesis or CVS on more than 5% of pregnant women of all ages. That, however, would be unacceptable because of the cost:benefit ratio and the potential for complications. 

The only way to detect 100% of DS cases is to perform CVS or amniocentesis in every pregnancy. And we would then be practicing case detection, not screening. 

Many patients don't understand that genetic screening doesn't come with a guarantee. Yes, the consent forms they sign explain that truth. But emotionally, most mothers-to-be want to believe that detection is 100% accurate. All too often, we succumb to the desire to provide more good news than the data may warrant. Patients, too, are complicit in asking the same question in different ways: What are my results? Could the test be wrong? Have you ever seen a problem with this test? Rather than saying "Don't worry," perhaps a dose of caution would be more prudent.  

We need to remember that screening is screening; it's great, but not perfect.

Sign Out: Prenatal screening isn't perfect

 Editorial Board member Joe Leigh Simpson, MD, attended and spoke at last month’s FIGO meeting in Malaysia. This is his personal account of the conference highlights. 

More than 8,000registrants gathered inKuala Lumpur, Malaysia,November 5 to 10, 2006,for the XVIII FIGO WorldCongress of Gynecologyand Obstetrics. With its110 national membersocieties, FIGO providesa forum for scientificadvances and also hasinstituted many initiativesto improve women’shealth worldwide. All ofthe organization’s effortswere on display at thetriennial meeting.			

Paul Van Look, Khalid J. Khan, and Ahmet Metin Gulmezoglu, all of the World Health Organization (WHO), reviewed specific causes of maternal death. Of all maternal deaths, 29% result from hemorrhage, 20% from infection, 19% from preeclampsia/eclampsia, and 12% from unsafe abortion.  

Using a WHO worldwide audit (Khan KS, et al. 

. 2006;367:1066), Dr. Gulmezoglu reported that hemorrhage was the most common cause of death in both Africa (34%) and Asia (31%). In Latin America and the Caribbean, hypertensive disorders were most prevalent (26%). Abortion deaths were the highest in Latin America and the Caribbean, accounting for as many as one third of maternal deaths in these countries. Of great importance is that the leading cause of anemia in Sub-Saharan Africa is malaria. It accounts for 60% of cases. Malaria is responsible for 10,000 maternal deaths per year, as a result of either preeclampsia or vulnerability to hemorrhage secondary to anemia. 

To begin to reduce maternal mortality, FIGO has targeted pilot projects to selected low-income countries (Haiti, Kenya, Kosovo, Pakistan, Peru, Moldova, Nigeria, Geri, Uganda, Ukraine, and Uruguay). In each area, FIGO and the national and local societies collaborate. 

Professor Van Look touted marked improvements in some countries, in particular FIGO host Malaysia and other rapidly developing countries in Asia; however, maternal mortality in Africa is disappointingly unchanged, placing in doubt the MDG-5 goal. Dr. Van Look posited that the high rate of maternal mortality is not likely to change unless intermediate causes are addressed. These include low use of contraception, lack of availability of obstetrical surgery (cesarean delivery [CD]), and lack of a skilled birth attendant. CD rates are less than 1% in many low-income countries with high maternal mortality, whereas rates of 5% to 15% are considered necessary to minimize maternal mortality.  

Given the high prevalence of postpartum hemorrhage, FIGO has specifically targeted this cause of maternal mortality. Dr. Pisake Lumbegana (Thailand) reviewed encouraging efforts in Asia, applying guidelines that reflect joint recommendations of the International Confederation of Midwives (ICM) and FIGO. Foremost in preventing postpartum hemorrhage is active management of the third stage of labor. Even when a skilled birth attendant is present, as in the United States, active management still reduces blood loss and need for blood transfusion. In developing countries, these measures can be lifesaving.  

It is recommended that oxytocin and other uterotonic drugs be administered within 1 minute 

 birth, along with controlled cord traction and uterine massage. If a skilled birth attendant is not present, controlled cord traction is not recommended, but uterine massage is begun immediately after passage of the placenta. If oxytocin is unavailable or the birth attendant has limited skills, misoprostol is recommended after birth of the baby. The dose is 100 mg orally or sublingually, and should not be repeated. Shivering and pyrexia are common side effects.  

FIGO and ICM also have embarked upon teaching home-based lifesaving skills. However, knowledge is still limited in many countries, and the failure to fully implement recommendations of ICM and FIGO is a disappointment. Also discussed were several novel methods to treat postpartum hemorrhage that are not likely to be used in the US. These include devices prefilled with oxytocin for injection in the umbilical cord, methods of uterine tamponade, and nonpneumatic anti-shock garments. Uterine B-Lynch sutures continue to be used, with apparent benefit.  

Mitigating deleterious effects of postpartum hemorrhage is an adequate hemoglobin level at delivery, thus aggressive administration of iron is recommended for women who are iron-deficient. In many countries, diagnosis is now based on serum ferritin and transferrin receptor (Tfr) levels. Serum ferritin below 12 μg/L indicates iron deficiency, but the most sensitive measure is serum TfR. Serum TfR concentrations are inversely related to the amount of iron stores. TfR levels become elevated before changes in either serum ferritin or mean corpuscular volume (MCV).  

Highlights of the XVIII FIGO World Congress (XML)

Making sense of the CF screening guidelines 

 The latest official guidelines on cystic fibrosis screening   have some clinicians bewilderedand others looking for an easy way to put   them to good use. A top expert in the field provides practical advice on how   to individualize the recommendations. 

The viscous secretions that accumulate in the pulmonary and pancreatic ducts   of patients with cystic fibrosis (CF) can cause chronic obstructive lung disease,   pancreatic enzyme deficiencies, and all the clinical complications that accompany   these two defects. 

 The disease's pathogenesis centers around a defect in a chloride channel that   is essential for excreting chloride and inhibiting sodium uptake in epithelial   cells (Figure 1). This common autosomal-recessive disorder occurs in all ethnic   groups but is especially prevalent in Caucasians of Ashkenazi Jewish or European   ancestry, affecting one in 3,300; one in 27 is a heterozygotic carrier.

   The disease occurs much less frequently in African-Americans, Asians, and Hispanics.

   Over 30,000 Americans have severe CF, and 8 to 9 million are heterozygotes. 

PLEASE NOTE: If you are using Internet Explorer version 6 or   higher, after clicking to enlarge the graphic, click the picture icon that appears   in the lower right-hand corner of the graphic. 

Because of CF's high prevalence and severity, The American College of Obstetricians   and Gynecologists now recommends genetic screening for all asymptomatic women.   Guidelines promulgated in 2001 have led ob/gyns to develop individual office   procedures to help implement these recommendations.

 My purpose here   is to review the guidelines and their rationale, and to suggest ways to apply   these in the real world of clinical practice. 

 Although CF is a severe disease, not all affected individuals show pulmonary   and pancreatic manifestations. Mean life expectancy is 30 to 35 years, and has   increased only slightly over the last few decades.

 In the United   States, a significant portion of lung transplants and heart/lung transplants   are now done on patients with the disease. The disorder usually produces clinical   signs and symptoms in early childhood, but 10% to 20% of affected individuals   are detected at birth because of meconium ileus. 

 Increasing accumulation of viscous secretions can gradually bring on chronic   respiratory obstruction, while blocked pancreatic ducts and the subsequent poor   intestinal absorption often cause malnutrition and postnatal growth retardation.   Almost all males with CF have azoospermia, the anatomic result of congenital   bilateral absence of the vas deferens. The "gold standard" for diagnosis remains   the chloride sweat test, although clinicians increasingly use molecular confirmation   as well. Once one of the mutations discussed further on is recognized in a family,   molecular studies can detect heterozygotes and affected relatives. 

 The CF geneofficially called the Cystic Fibrosis Transmembrane Regulator   (CFTR)was cloned in 1989.

 Located on the long arm of chromosome   7, it consists of 27 exons. Given its large size, opportunities exist for many   mutations to develop, all of which could ultimately result in a dysfunctional   or absent gene product; about 1,000 different mutations have already been recognized.   Molecular tests can readily detect a specific mutation, and willing vendors   can sequence the entire gene. Keep in mind, however, that CFTR mutations will   still not be found in all affected or heterozygous individuals. A test's sensitivity   for finding a mutation in a known heterozygote varies by ethnic background. 

 In most populations, the most common mutation involves a deletion (

)   of the three nucleotides at codon 508, resulting in the loss of the amino acid   phenylalanine (F)

F508 (Figure   2). The most common defect in Ashkenazi Jews involves a nucleotide mutation   in the codon that usually results in the amino acid tryptophan (W). In this   mutation, a stop codon (X) is inappropriately present at position 1282W1282X,   resulting in the absence of a functional CFTR gene product. Among the many other   mutations, only 20 to 25 occur as frequently as 1 per 1,000 (0.1%) in the general   population.

 Taking a close look at the history of CF screening 

 Given the high prevalence of CF, screening seemed likely to be offered soon   after the gene was cloned in 1989. But the situation immediately proved more   complicated than was the case with sickle cell anemia, the prototypic molecular   disorder. In the latter case, virtually all mutations are caused by a single   point mutation (codon 6), which results in the hemoglobin sickling. In contrast,   CF is characterized by molecular heterogeneity, as witnessed by the 1,000 known   mutations. Although 

F508 was recognized   as the most common mutation, the extent to which it contributes to the clinical   syndrome varies widely from population to population. In Caucasians of northern   European descent, including the British, 70% or more of all CF mutations are   due to 

F508 is identified in only 50%   to 55%, and in some Slavic populations barely 25%. 

This heterogeneity means that population screening would be inefficient if we only tested for 

F508. It would only detect about 60% of CF chromosomes, in heterozygous or homozygous form. Screening only for 

F508 would leave many couples in the anxious position of knowing that one partner is heterozygous, but unable to exclude the other as a carrier. Worse yet, fetal diagnosis would not be possible through amniocentesis or chorionic villi analysis because there is no biochemical assay for the protein gene product.

 Plans for CF screening were thus put on hold pending molecular advances and   studies assessing receptivity of patients. On the molecular front, work began   that eventually led to identification of some 1,000 CF mutations. Most are rare,   but aggregate screening for 23 specific mutations can detect 97% of CF mutations   in Ashkenazi Jews, 80% in Caucasians of European ancestry, and lower frequencies   in Hispanic, Asian, and African-Americans (Table 1). Researchers have shown   that CF screening could be performed without undue alarm, and that patients   want it. The positive experience with Tay-Sachs disease should apply equally   to CF. The consensus developed that once 80% or more of CF cases could be detected   (vs. 60% with 

F508 CF testing alone),   population screening would become attractive. 

In 1997 an NIH consensus conference considered laboratory, epidemiologic, and sociologic data and finally recommended population screening for cystic fibrosis.

 Yet, the conference provided no specific instructions on how to carry through on this recommendation. Nonetheless, the report spurred development of a task force consisting of representatives from the NIH Human Genome Center, ACOG, and the American College of Medical Genetics (ACMG). The task force developed guidelines, created patient brochures, and generated public education materials. They recommended a panel of 25 mutations for screening, including 

 In 2004, two of these mutations were dropped, leaving the current recommendation at 23 mutations. 

 to Caucasians of Ashkenazi Jewish or European descent while it should be 

 in other ethnic groups. Distinctions between "made available" and "offered" were not provided. 

 Once these guidelines were introduced in 2001,

 ob/gyns began   introducing CF screening in their own practices. CF thus joined other genetic   disorders for which ACOG recommended population screeningTay-Sachs disease   and Canavan disease in Ashkenazi Jews, sickle cell anemia in African-Americans,   ß-thalassemia in individuals of Southern Mediterranean heritage (e.g.,   Greek, Italian, Cypriot), and 

-thalassemia   in certain Asians (e.g., Vietnamese, Chinese, Filipino).

Of course the sudden introduction of any screening policy can generate confusion and unexpected consequences, so gradual introduction of CF screening was considered wise. By 2004, practices had the opportunity to develop their own tailored protocol. Screening ideally should occur before pregnancy, but typically takes place postconception. This should occur early enough to allow patients time for various reproductive options. One must first exclude couples with a positive family history, for CF screening as described here is applicable only to those with a negative family history. (If a relative has CF, obtain records or refer the couple to a geneticist who can determine the molecular basis. His or her recommendations are likely to involve looking for that particular mutation in your patient or her husband. The partner with the negative family history can be screened with a standard CF panel.)

Fulfilling ACOG/ACMG guidelines for the 23 mutations is possible through several vendors. Costs typically are $150 to $300. Some offer larger panels, screening 35 to over 70 mutations. Panels that screen for more than the 23 mutations aren't necessary if there's a negative family history: Few additional heterozygotes are detected beyond the one in 27 expected in Caucasians.

However, using an extended panel is not unreasonable. If that's the approach you choose, it's best to manage every patient in your practice similarly. Similar reasoning applies to so-called ethnic-specific panels. Again, detection rates are currently only marginally improved over the standard CF panel, but ethnic-specific panels may be valuable if a positive family history exists.

 It is advisable that every   practice develop a protocol for CF screening. No single protocol is universally   applicable, but consistency is crucial. One way to document compliance is to   develop a written protocol to which all staff adhere. A key decision is whether   to simultaneously screen the prospective mother and father or screen only the   mother and then the father if the former is a carrier (the sequential approach).   Either approach is acceptable. Screening both parents obviously produces the   highest detection rate, although not by much (Table 2). The downside is that   one partner will be a carrier twice as often, generating more anxiety and requiring   follow-up more often. Keep in mind, though, that in both concurrent and sequential   screening, you still won't detect every CF mutation. 

 Suppose a patient or her spouse has a severe CF-causing   mutation like 

F508. Relatives of   your patient could well have inherited the same mutation from a common ancestor.   The likelihood is 50% that any one of your patient's siblings or her partner's   siblings will have the same mutation. As caring physicians, we want to alert   at-risk individuals; however, we have no authority to contact a relative directly.   The solution is using a sample letter, mailed not by the physician but by the   patient or her spouse. This letter would inform relatives of the consequence   of a CF mutation having been detected. A template for such a letter exists in   the ACOG/ACMG booklet, 

Preconception and Prenatal Carrier Screening for Cystic   Fibrosis

Does CF screening perform as predicted? Yes. One large study involving Kaiser Permanente California screened 27,000 women.

 The heterozygote frequency expected was 1 in 28; 1,000 affected fetuses were detected. The costs of screening equaled the projected cost of caring for affected liveborns, which were avoided by patients exercising reproductive options.

"Offering" the test panel vs. "making it available."

 Which patients   should be screened? ACOG/ACMG guidelines state that screening should be offered   to Caucasians of European and Ashkenazi Jewish ancestry. There is no further   instruction, but it is reasonable to assume that the approach should be similar   to that used in Tay-Sachs disease, sickle cell anemia, or ß- and 

-thalassemia.   But first, clinicians must start a dialogue with their patients. Remember that   genetic screening is never obligatory, as it might be for Rh(D) screening. A   patient brochure produced by ACOG can help you review the inheritance of CF,   variability of CF symptoms, and likelihood of detecting carrier status. This   brochure explicitly states that not all CF mutations are detectable, and, hence,   not all affected individuals can be detected. In other words, false-negative   cases are unavoidable. We can't overemphasize the legal significance of this   statement. 

In couples of African-American, Hispanic, and Asian origin, CF screening should be "made available." Unfortunately the distinction between "offering" and "made available" isn't very clear. Perhaps a brief informative statement about CF could be followed by explaining to the patient that CF screening exists, and that information through brochures or other sources can help her decide if she should pursue  it further. The ACOG/ACMG brochure, 

Cystic Fibrosis Carrier Testing: The Decision is Yours,

 can be helpful. Some physicians find that it is unwieldy to handle patients of different ethnicities within a given practice. In many multiethnic practices it may be difficult to stratify patients by ethnic group. 

 How should you document compliance with the guidelines? Adhere to a consistent plan of verifying that the screening information has been conveyed. This might consist of  a written note in the chart, or retention of written informed consent stating the patient's choice.  A sample consent form exists in  the ACOG patient information brochure mentioned previously; however, retaining such a form on every patient might be burdensome, especially if an office uses an electronic medical record. 

 If CF tests on both partners are negative, no further evaluation is required. Be certain each couple realizes that 100% carrier detection is never possible in general screening (Table 1). If, on the other hand, one partner has a mutation, but the other screens negative, no further evaluation is needed. The residual risk of still having a CF fetus is low but finite (Table 2).

Genetic counseling is not ordinarily required, but some patients may request it. If one partner proves to be a CF carrier and the other is not tested, the risk is not inconsequential. In Europeans of Caucasian origin, the residual risk is one in 116. One approach is chorionic villi or amniotic fluid analysis to exclude the known mutation.

If both couples are heterozygous for the same or for two different deleterious alleles (compound heterozygotes), refer them to a geneticist. The risk of an affected fetus is 25%, and options for a definitive diagnosis should be presented.

Cystic Fibrosis Testing: What Happens if Both my Partner and I are Carriers?

 can be useful at this stage of screening.

 In intron 8 (the noncoding regions between   exons 8 and 9) a polymorphism exists that's relevant to CF. (A polymorphism   is an alternate form of a gene, examples being blood groups A, B, or O, or the   various HLA alleles.) The CF polymorphism involves the presence of either 5,   7, or 9 thymidines (5T, 7T, 9T) at a certain position. If the 5T allele is present,   splicing the noncoding intron from the coding exon becomes inefficient on that   chromosome. With 5T, the amount of CF proteinthe gene productis   approximately 50% of normal. By contrast, in 

F508   and W1282X virtually no CFTR gene product is synthesized. In other words, 5T   by itself is not sufficiently harmful to produce severe CF, with pulmonary and   pancreatic disease. But 5T may cause congenital bilateral absence of the vas   deferens (CBAVD) if present in homozygous form, or if present in compound heterozygosity   along with a more severe CFTR mutation like 

 If the sole purpose of CF in population screening were to exclude pancreatic   and pulmonary disease, testing for the 5T polymorphism would not be required.   The rationale is that CBAVD is not a severe form of CF. However, if 5T exists   on the same chromosome (i.e., cis) as a particular second mild mutation (specifically   the point mutation R117H), the combination becomes comparable to a severe CF   mutant allele like 

F508; very little   CFTR is synthesized: 

  If 5T exists on the same chromosome as R117H and the other chromosome   has another severe mutation (

  If 7T is present on the same chromosome as R117H, the fetus is only   at risk for mild CF, even if the allele on the other chromosome is 

F508.   CBAVD will result, but not severe CF. 

  If both chromosomes show 5T (homozygosity), and there is no other CF   mutation, CBAVD can exist but not severe CF. 

In consideration of the above, labs routinely test (reflex) for 5T whenever R117H is detected. Otherwise, 5T will not be sought. If a physician wishes to know the status of 5T polymorphisms, for example in a workup for male infertility, he or she must specifically request it.

 In summary, physicians should offer CF screening to Caucasians of European   or Ashkenazi Jewish ancestry and make the test available to other ethnic groups.   Although it's best to screen a nonpregnant patient, it usually doesn't happen   that early on. A specific panel of mutations is now recommended by ACOG/ACMG,   encompassing the relatively common 

F508   and W1282X alleles and 21 less common mutations. This panel will detect most,   but importantly not all, carriers and, hence, affected fetuses. You have to   make patients realize that the screening test will not detect all carriers.   Patient information brochures may help you implement guidelines, and a standard   protocol should be followed in offices. 

 Dr. Simpson is on the scientific advisory board for Imetrikus. 

 1.	Grody WW, Cutting GR, Klinger KW, et al. Laboratory   standards and guidelines for population-based cystic fibrosis carrier screening.

Preconception and Prenatal Carrier   Screening for Cystic Fibrosis.

 Washington DC; The American College of Obstetricians   and Gynecologists, 2001. 

The latest official guidelines on cystic fibrosis screening have some clinicians bewildered--and others looking for an easy way to put them to good use. A top expert in the field provides practical advice on how to individualize the recommendations.